JP2019172689A - Extended release of neuregulin for treating heart failure - Google Patents

Abstract

To provide methods for preventing, treating or delaying cardiovascular diseases or disorders.SOLUTION: The present invention provides methods and kits for preventing, treating or delaying various cardiovascular diseases or disorders, especially heart failure, by extended release of neuregulin to a mammal. Moreover, the extended release of neuregulin is administered by subcutaneous infusion with a pump.SELECTED DRAWING: None

Description

This application claims the benefit of priority of US Provisional Application No. 61 / 826,433, filed May 22, 2013, the entire contents of which are incorporated herein by reference. Yes.

This application contains a sequence listing that is submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. The ASCII copy created on May 20, 2014 was 11
It is called 748-039-228_SL.txt and the size is 3,198 bytes.

(Field of Invention)
The present invention relates generally to compositions and methods for preventing, treating or delaying various cardiovascular diseases or disorders, particularly heart failure, by sustained release of neuregulin. In particular, the present invention relates to the administration of neuregulin to a mammal via subcutaneous injection by a pump.

(Background of the Invention)
Heart failure affects approximately 5,000,000 Americans and more than 550,000 new patients are diagnosed with the condition each year. Current pharmacotherapy for heart failure is mainly angiotensin converting enzyme (
Although directed towards ACE) inhibitors, they are vasodilators that dilate blood vessels, lower blood pressure, and reduce cardiac workload. Although the rate of mortality reduction is significant, the actual mortality reduction with ACE inhibitors averages only 3% to 4% and has some potential side effects.
Further limitations are associated with other options for preventing or treating heart failure. For example, heart transplantation is clearly more expensive and invasive than drug treatment, which is further limited by donor heart availability. The use of mechanical devices such as biventricular pacemakers is similarly invasive and expensive. Therefore, there is a need for new therapies that take into account the shortcomings of current therapies.

One promising new therapy involves the administration of neuregulin (hereinafter “NRG”) to patients suffering from or at risk of developing heart failure. NRG, a family of EGF-like growth factors, includes NRG1, NRG2, NRG3, and NRG4, and a family of structurally related growth factors and differentiation factors including their isoforms, and numerous biological responses:
Differentiation of breast cancer cells and stimulation of milk protein secretion; induction of differentiation of neural crest cells into Schwann cells;
It is involved in stimulating acetylcholine receptor synthesis in skeletal muscle cells; and in promoting cardiomyocyte survival and DNA synthesis. In vivo studies of neuregulin gene-targeted homozygous mouse embryos with severe defects in myocardial trabeculogenesis and dorsal root ganglion development indicate that neuregulin is essential for heart and nerve development

NRG binds to the EGF receptor family, including EGFR, ErbB2, ErbB3, and ErbB4, each of which plays an important role in multiple cellular functions including cell growth, differentiation, and survival. They are protein tyrosine kinase receptors consisting of an extracellular ligand binding domain, a transmembrane kinase domain, and a cytoplasmic tyrosine kinase domain. NRG ErbB3
Or after binding to the extracellular domain of ErbB4, it induces structural changes that result in heterodimer formation between ErbB3, ErbB4, and ErbB2 or homodimer formation between ErbB4 itself, thereby Phosphorylation of the inner receptor C-terminal domain occurs. The phosphorylated intracellular domain then binds to additional signal proteins in the cell and the corresponding downstream
Activates the AKT or ERK signaling pathway and induces a series of cellular responses such as cell proliferation, cell differentiation, cell apoptosis, cell migration, or stimulation or reduction of cell adhesion. Of these receptors, mainly ErbB2 and ErbB4 are expressed in the heart.

The EGF-like domain of NRG-1 ranging in size from 50 to 64 amino acids has been shown to be sufficient to bind to and activate these receptors. From previous research,
Neuregulin-1β (NRG-1β) has been shown to be able to bind directly to ErbB3 and ErbB4 with high affinity. The orphan receptor ErbB2 is an ErbB3 homodimer or ErbB
Heterodimers can be formed with ErbB3 and ErbB4 with higher affinity than 4 homodimers. Neural development studies have shown that complete NRG-1β, ErbB2, and ErbB3
It has been shown that a signal transduction system is required. Targeted destruction of NRG-1β or ErbB2 or ErbB4 resulted in embryonic lethality due to abnormal development of the heart. Recent studies have also revealed the role of NRG-1β, ErbB2, and ErbB4 in cardiovascular development and maintenance of normal adult cardiac function. NRG-1β has been shown to enhance sarcomere organization in adult cardiomyocytes. Slow release of NRG via intravenous infusion significantly improves or significantly protects against worsening myocardial performance in different animal models of heart failure as well as clinical trials. These results make NRG-1 promising as a lead compound for the treatment of heart failure. Administration of NRG to patients via intravenous infusion on consecutive days at admission is somewhat inconvenient and expensive, but to prevent, treat or delay cardiovascular disease, especially heart failure
There is a need to develop an effective and simple method of using NRG.

(Summary of Invention)
The Applicant has discovered that sustained release of neuregulin (NRG) by intravenous infusion greatly improves the effectiveness of NRG in the treatment of heart failure compared to NRG administered by a non-sustained release method. The sustained release of NRG by intravenous infusion also has the benefit of reducing the adverse side effects of NRG compared to NRG administered by a non-sustained release method. The present invention further provides compositions and methods for the prevention, treatment or delay of various cardiovascular diseases or disorders, in particular heart failure, by sustained release of NRG by subcutaneous injection into mammals, particularly humans. In particular, the present invention relates to compositions and methods for preventing, treating or delaying various cardiovascular diseases or disorders, particularly heart failure, by sustained release of NRG using a portable minipump for subcutaneous infusion.

Applicants have discovered that NRG enhances cardiomyocyte differentiation and organization of sarcomeric and cytoskeletal structures, as well as cell adhesion. The Applicant has also discovered that NRG by intravenous infusion significantly improves or prevents the deterioration of myocardial performance in different animal models and clinical trials of heart failure.
Neuregulins, neuregulin polypeptides, neuregulin derivatives, or compounds that mimic the activity of neuregulin are included within the scope of the present invention.

Accordingly, in a first aspect of the invention, there is provided a method for preventing, treating or delaying various cardiovascular diseases or disorders, particularly heart failure, comprising providing sustained release of neuregulin to a mammal in need thereof. Provided. In one embodiment of this method, neuregulin sustained release to the mammal increases the left ventricular EF value of the mammal. In another embodiment of the method, the sustained release of neuregulin to the mammal is left ventricular end diastolic volume (LVEDV) or left ventricular end systolic volume (LV
Reduce ESV). In another embodiment of the method, sustained release of neuregulin to the mammal improves walking distance and quality of life for 6 minutes. In another embodiment of the method, sustained release of neuregulin to the mammal reduces side effects. In some embodiments of the method for preventing, treating or delaying a cardiovascular disease or disorder in a mammal, sustained release of neuregulin to the mammal includes the use of a minipump. In some embodiments of the method, the sustained release of neuregulin to the mammal is administered by subcutaneous injection.

In a second aspect, a neuregulin sustained release composition or formulation is provided for the prevention, treatment or delay of various cardiovascular diseases or disorders, particularly heart failure. In one embodiment, the use of a neuregulin composition or formulation increases the left ventricular EF value of a mammal. In another embodiment, the use of a neuregulin composition or formulation reduces left ventricular end diastolic volume (LVEDV) or left ventricular end systolic volume (LVESV). In another embodiment, the use of a neuregulin composition or formulation improves 6 minutes walking distance and quality of life. In another embodiment, the use of a neuregulin composition or formulation reduces side effects. In some embodiments, the neuregulin sustained release composition or formulation is administered by subcutaneous infusion with a pump, such as a syringe pump. In some embodiments, the syringe pump is a minipump. In a further embodiment, the minipump is an insulin pump.

In a third aspect, an effective amount and / or a range of effective amounts of sustained release neuregulin is provided to prevent, treat or delay various cardiovascular diseases or disorders, particularly heart failure. In some embodiments, neuregulin is administered by subcutaneous injection. In some embodiments, the effective amount of neuregulin is 0.3 μg / kg. In some embodiments, the effective amount of neuregulin is 1.2 μg / kg. In some embodiments, the effective amount of neuregulin is 2.0 μg / kg. In some embodiments, the effective amount of neuregulin is 3
0.0 μg / kg. In some embodiments, the effective dose range of neuregulin ranges from 0.3 to 3.0.
μg / kg. In some embodiments, the effective dose range of neuregulin ranges from 1.2 to 2.0 μ.
g / kg.

In a fourth aspect, the present invention provides a kit comprising a neuregulin composition or formulation and a portable minipump. In some embodiments, the kit further comprises instructions for using the kit for the prevention, treatment or delay of heart failure in a mammal. In some embodiments, the portable minipump is an insulin pump.

(Brief description of the drawings)
Figure 1: LVEF% results at baseline and 30 days.

Figure 2: Change in absolute value of LVEF% at 30 days compared to baseline.

Figure 3: LVEDV results at baseline and on day 30.

Figure 4: LVEDV absolute value change on day 30 compared to baseline.

Figure 5: LVESV results at baseline and on day 30.

Figure 6: Change in absolute value of LVESV on day 30 compared to baseline.

Figure 7: Result of increased walking distance on day 30 compared to baseline.

Figure 8. Results of dyspnea after walking on day 30 compared to baseline.

Figure 9: Post-walking fatigue results on day 30 compared to baseline.

Figure 10: Change in quality of life score on day 30 compared to baseline.

Figure 11: Percentage of NYHA classification at baseline and day 30.

(Detailed description of the invention)
(A. Definition)
For purposes of clarity of disclosure and not limitation, the following detailed description of the invention is divided into the following subsections. All publications mentioned herein are incorporated by reference to disclose and explain the methods and / or materials to which the publications are cited in connection with them.

(Definition)
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, applications, published applications, and other publications mentioned herein are incorporated by reference in their entirety.
If the definitions shown in this section contradict or otherwise contradict the definitions shown in patents, applications, published applications, and other publications incorporated herein by reference, the definitions shown in this section Overrides the definitions incorporated herein by reference.

As used herein, the singular form “a”, “an”, unless expressly indicated otherwise in the text.
And “the” means “at least one” or “one or more”.

を含むNRG-1 β2アイソフォームの177〜237残基を含むペプチドがある。NRG-1 β2アイソ
フォームの177〜237残基を含むペプチドは、前記受容体に結合しかつこれを活性化するの
に十分であることが証明されている、EGF様ドメインを含む。 As used herein, “neuregulin” or “NRG” as used herein refers to ErbB2,
Refers to proteins or peptides that can bind to and activate ErbB3, ErbB4, or a combination thereof, including but not limited to all neuregulin isoforms, neuregulin EGF-like domains Only include polypeptides comprising neuregulin EGF-like domains, neuregulin variants or derivatives, and any type of neuregulin-like gene product that also activates the above-described receptors, as detailed below. Neuregulin also includes NRG-1, NRG-2, NRG-3, and NRG-4 proteins, peptides, fragments, and compounds that mimic the activity of neuregulin. Neuregulin used in the present invention activates the ErbB receptors described above to modulate their biological responses, eg, stimulates acetylcholine receptor synthesis in skeletal muscle cells; and / or heart cells Differentiation,
Survival and DNA synthesis can be improved. Neuregulin also includes those variants with conservative amino acid substitutions that do not substantially alter their biological activity. Suitable conservative substitutions of amino acids are known to those skilled in the art and can usually be made without altering the biological activity of the resulting molecule. One skilled in the art recognizes that single amino acid substitutions in non-essential regions of a polypeptide generally do not substantially alter biological activity (eg, Wa
tson et al., “Molecular Biology of the Gene”, 4th edition, 1987
(See The Bejacmin / Cummings Pub. Co., P. 224). In a preferred embodiment, the neuregulin used in the present invention binds to and activates ErbB2 / ErbB4 or ErbB2 / ErbB3 heterodimers, including but not limited to the amino acid sequence:

There are peptides containing residues 177 to 237 of the NRG-1 β2 isoform containing. A peptide comprising residues 177-237 of the NRG-1 β2 isoform contains an EGF-like domain that has been shown to be sufficient to bind to and activate the receptor.

；アミノ酸残基177-240

)、その各々は、本発明のニューレグリンの例であると考えられる。ある実施態様では、E
GF様ドメインは、NRG-2の受容体結合ドメインのアミノ酸配列を含む。ある実施態様では
、EGF様ドメインは、NRG-3の受容体結合ドメインのアミノ酸配列を含む。ある実施態様で
は、EGF様ドメインは、NRG-4の受容体結合ドメインのアミノ酸配列を含む。ある実施態様
では、EGF様ドメインは、米国特許第5,834,229号に記載されているような、

というアミノ酸配列を含む。 As used herein, an “epidermal growth factor-like domain” or “EGF-like domain” is an Erb
WO 00/64400, Holmes et al. (Science, 2), which binds to and activates B2, ErbB3, ErbB4, or combinations thereof, the contents of which are all incorporated herein by reference.
56: 1205-1210 (1992)); US Pat. Nos. 5,530,109 and 5,716,930; Hijazi et al. (Int. J. Oncol., 13: 1061-1067 (1998)); Chang et al. (Nature, 387). : 509-512 (
1997); Carraway et al. (Nature, 387: 512-516 (1997)); Higashiyama et al. (J
Biochem., 122: 675-680 (1997)); and EG as disclosed in WO 97/09425.
Refers to the polypeptide motif encoded by the neuregulin gene that has structural similarity to the F receptor binding domain. In certain embodiments, the EGF-like domain is ErbB2 / ErbB4.
Alternatively, it binds to and activates ErbB2 / ErbB3 heterodimers. In some embodiments, EG
The F-like domain includes the amino acid sequence of the receptor binding domain of NRG-1. In some embodiments, the EGF-like domain comprises an amino acid sequence corresponding to amino acid residues 177-226, 177-237, or 177-240 of NRG-1 (amino acid residues 177-226

Amino acid residues 177-240

Each of which is considered to be an example of a neuregulin of the present invention. In some embodiments, E
The GF-like domain includes the amino acid sequence of the receptor binding domain of NRG-2. In certain embodiments, the EGF-like domain comprises the amino acid sequence of the receptor binding domain of NRG-3. In certain embodiments, the EGF-like domain comprises the amino acid sequence of the receptor binding domain of NRG-4. In one embodiment, the EGF-like domain is as described in U.S. Patent No. 5,834,229,

The amino acid sequence is included.

Neuregulin protein is for oral, topical, inhalation, buccal (e.g. sublingual), parenteral (e.g. subcutaneous, intramuscular, intradermal, or intravenous), transdermal administration or other suitable route of administration. It can be formulated. The most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular neuregulin protein used. Neuregulin protein can be administered alone. Alternatively, preferably the neuregulin protein is co-administered with a pharmaceutically acceptable carrier or excipient. Any suitable pharmaceutically acceptable carrier or excipient can be used in the present methods (eg, “Remington: The Science and Pra
ctice of Pharmacy) ", Alfonso R. Gennaro, Mack Publishing Company, April 1997;
And “Remington's Pharmaceutical Sciences”, 18th Edition, Gennar
(See o, Mack Publishing Co. (1990)).

As used herein, a “pump” is a therapeutic fluid, drug, protein, and / or
Or a drug delivery device that uses the subcutaneous injection of other compounds and has the property of continuous and precise dosing of the medication in their supply. The pump can use a hypodermic catheter for continuous subcutaneous infusion. The catheter may be external or the catheter port may be incorporated into the pump mechanism. A minipump is a device that can accurately transport liquids, which is portable and easy to handle. By way of example, an insulin pump is a medical device used to administer insulin or other substances in the treatment of diabetes or other diseases, also known as continuous subcutaneous insulin infusion therapy. The insulin pump can be configured to connect to a disposable thin plastic tube or catheter through which insulin or other drug substance is passed to the tissue. The catheter is inserted subcutaneously and can be replaced as needed. The pump can be configured in an external device connected to the patient and configured in an implantable device that is implanted in the patient's body. An external pump can include a device designed for use in a fixed location, such as a hospital, clinic, or similar location, and can also be a pump designed to be carried by a patient or It can include devices configured for walking or portable use, such as the like. External pumps include containers of liquid media, such as, but not limited to, liquid media containing neuregulin protein.

The external pump can be connected to the fluid flow communication path to the patient, for example by a suitable hollow tube.
The hollow tube may be connected to a hollow needle that is designed to penetrate the patient's skin and deliver a liquid medium therethrough. Alternatively, the hollow tube can be connected directly to the patient by a cannula or the like. The external pump can be mounted or otherwise mounted on or under the patient's clothing. Examples of suitable pumps include MiniMed Paradigm 522 insulin pump, MiniMed Paradigm 722 insulin pump, MiniMed Paradigm 515 insulin pump, MiniMed Paradigm 715 insulin pump, MiniMed Paradigm 512R insulin pump, MiniMed Paradigm 712R insulin pump, MiniMed 508 insulin pump, MiniMed
d 508R insulin pump (Medtronic; Northridge, CA), as well as any similar device known to those skilled in the art, but not limited thereto.

Examples of external pump type delivery devices are “Infusion devices and methods with disposable parts”.
vice And Method With Disposable Portion), filed on August 23, 2005, US2
Published as 006/0264894 and issued as U.S. Pat.
11 / 211,095, as well as “Exchangeable Electron Card for Infusion Device”
PCT Publication WO 01/70307 (PCT / US01 / 09139) entitled `` IC Cards For Infusion Devices) ''
), "Components And Methods For Patient Infusio
PCT Publication WO 04/030716 (PCT / US2003 / 028769), PCT Publication WO entitled “Dispenser Components And Methods For Infusion Device” 04/030717 (PCT / US2003 / 029019), entitled "Method For Advising Patients Concerning Doses Of Insulin",
U.S. Patent Application Publication No. 2005/0065760, as well as "Wearable Self-Injecting Drug Injection Device
US Pat. No. 6,589,229, entitled “Self-Contained Drug Infusion Device”, each of which is incorporated herein by reference in its entirety.

Pharmaceutically acceptable compositions that can be utilized for use in the present invention and methods related to their administration are described in US Pat. Nos. 5,736,154; 6,197,801; 5,741,511; 5,886,039; 5,941,868; Including, but not limited to, those disclosed in US Pat. No. 6,258,374; and 5,686,102.

It should be noted that one skilled in the art, such as the attending physician, knows how and when to terminate, discontinue, or adjust to lower doses due to toxicity or adverse effects. Conversely, the physician will also know how and when to adjust the treatment to a higher level if the clinical response (excluding toxic side effects) is not appropriate.

In practical applications, neuregulin protein can be used alone or in combination with other substances,
In accordance with conventional pharmaceutical formulation techniques, β-cyclodextrin and / or 2-hydroxy-propyl-
It can be combined as an active ingredient intimately mixed with a pharmaceutical carrier or excipient, such as β-cyclodextrin. The carrier can take a wide variety of preparations which are desirable for topical or parenteral administration. Preparation of compositions for parenteral dosage forms such as intravenous injection or infusion include those known to those skilled in the art such as water, glycols, oils, buffers, sugars, preservatives, liposomes, stabilizers, Similar pharmaceutical media can be used, but not limited to these. Examples of such parenteral compositions include, but are not limited to, dextrose 5% w / v, normal saline or other solutions. Examples of buffers include, but are not limited to acetate, citrate and phosphate.
Examples of stabilizers include, but are not limited to, albumins such as human serum albumin, proteins such as gelatin, and the like. Examples of sugars include, but are not limited to, glucose (dextrose), sucrose, fructose, mannitol, sorbitol, and the like. Examples of salts include potassium bicarbonate, sodium bicarbonate, potassium chloride, sodium chloride,
And the like, but are not limited thereto. Examples of components of a pharmaceutical composition are described, for example, in the 1997 Remington literature cited above and the 1990 Remington literature cited above. The total dose of neuregulin protein to be administered alone or in combination with other substances can be administered in intravenous liquid vials in the range of about 1 ml to 2000 ml.

In another embodiment, the kit of the invention further comprises a needle or syringe, preferably packaged in sterile form, and / or a packaged alcohol pad for injection of the composition. Instructions for administration of the composition by the physician or by the patient are optionally included.

As used herein, unless clearly indicated otherwise in the text, “protein” means “
Synonymous with “polypeptide” or “peptide”.

As used herein, “activity unit” or “EU” or “U” means the amount of a standard that can induce a 50% maximal response. In other words, the EC50 must be measured to determine the activity unit of a given active agent. For example, a batch of products has an EC50 of 0.
If it is 1 μg, it is 1 unit. Furthermore, if using 1 μg of that product, 10
EU (1 / 0.1) is used. The EC50 can be determined by any method known in the art suitable for making such determinations, including the methods utilized by the inventors as identified herein. It is. The determination of such activity units is important for quality control of genetically engineered products and clinically used drugs, and it is important to quantify products from different pharmaceuticals and / or different batch numbers with a uniform standard. enable.

The following is an exemplary, rapid, sensitive, high flow rate, and quantitative NRG-1 biology through the combination of NRG and cell surface ErbB3 / ErbB4 molecules and indirect mediation of ErbB2 phosphorylation (E.g., Michael D. Sadick et al., 1996, Analytical Biochemistry).
, 235: 207-214, and WO03 / 099300).

）。HRGβ1（177〜244）の同一の試料を、該KIRA-ELISAと定量的抗ホスホチロシンウェス
タンブロット分析の両方で分析した場合、結果は互いに非常に密接に相関する。この報告
で記載されているアッセイは、HRGとErbB3及び／又はErbB4との相互作用から生じるErbB2
のチロシンリン酸化を特異的に定量化することができる。 Briefly, the assay is a kinase receptor activated enzyme-linked immunosorbent assay (KIRA-ELI
SA), which consists of two separate microtiter plates, one of which
For cell culture, ligand stimulation, and cell lysis / receptor solubilization, the other plate is for receptor capture and phosphotyrosine ELISA. The assay was developed for the analysis of NRG-induced ErbB2 activation and utilizes intact receptor stimulation on the surface of the adherent breast cancer cell line MCF-7.
Membrane proteins are solubilized by Triton X-100 lysis and the receptors are captured in ELISA wells coated with ErbB2-specific antibodies that do not cross-react with ErbB3 or ErbB4. The degree of receptor phosphorylation is then quantified by anti-phosphotyrosine ELISA. A reproducible standard curve is generated using an EC50 of about 36 OpM of heregulin β1 (177-244) (amino acid residues 177-24)
Four

). When identical samples of HRGβ1 (177-244) are analyzed by both the KIRA-ELISA and quantitative anti-phosphotyrosine Western blot analysis, the results correlate very closely with each other. The assay described in this report is based on ErbB2 resulting from the interaction of HRG with ErbB3 and / or ErbB4.
Can be specifically quantified.

Since most of the genetically engineered drugs are proteins and polypeptides, their activity can be determined by the active center formed by their amino acid sequence or their spatial structure. The activity titers of proteins and polypeptides are not consistent with their absolute quality and therefore cannot be determined in units of weight like the activity titers of chemicals. However, the biological activity of genetically engineered drugs is usually consistent with their pharmacodynamics, and the titer determination system established by a given biological activity determines its titer unit. can do. Therefore, the determination of biological activity can be part of the process of measuring the titer of substances with biological activity and is an important component of quality control of genetically engineered products . It is important to determine biological activity criteria for quality control of genetically engineered products and clinically used drugs.

The amount of standard product that can induce a 50% maximal response is defined as activity units (1 EU).
Therefore, products derived from different pharmaceuticals and products with different batch numbers can be quantified with a uniform standard.

As used herein, an “effective amount” of an active agent for the prevention, treatment or delay of a particular disease is a dosage sufficient to ameliorate or partially alleviate symptoms associated with the disease. is there. The dosage can cure the disease but is typically administered to ameliorate the symptoms of the disease.

In certain embodiments, the effective amount of neuregulin is at least 0.2 μg / kg / day, 0.3
μg / kg / day, 0.4 μg / kg / day, 0.5 μg / kg / day, 0.6 μg / kg / day, 0.7 μg / kg / day, 0.8 μg / kg / day, 0.9 μg / kg / day, 1.0 μg / kg / day, 1.1μg / kg / day, 1.2μg / kg / day, 1.3μg / kg / day, 1.4μg / k
g / day, 1.5 μg / kg / day, 1.6 μg / kg / day, 1.7 μg / kg / day, 1.8 μg / kg / day, 1.9 μg / kg / day, 2.0
μg / kg / day, 2.1 μg / kg / day, 2.2 μg / kg / day, 2.3 μg / kg / day, 2.4 μg / kg / day, 2.5 μg / kg / day, 2.6 μg / kg / day, 2.7 μg / kg / day, 2.8 μg / kg / day, 2.9 μg / kg / day, or 3.0 μg / kg / day. In one embodiment, the effective amount of neuregulin is 1.2 μg / kg / day.
In another embodiment, the effective amount of neuregulin is 2.0 μg / kg / day. In one embodiment, the effective amount of neuregulin is 3.0 μg / kg. In one embodiment, the effective dose range of neuregulin is 0.3-3.0 μg / kg / day. In one embodiment, the effective dose range of neuregulin is 1.2-2.0 μg / kg / day.

As used herein, an “active agent” is intended for diagnosis, cure, alleviation, treatment or prevention of disease in humans and other animals, or otherwise physical and mental health. Means any substance to enhance

As used herein, “amelioration” of the symptoms of a particular disorder by administration of a particular active agent is permanent, temporary, or persistent that may result from or be associated with administration of the substance. Or, it indicates a decrease regardless of whether it is transient.

As used herein, “treat”, “treatment”, and “treating” refer to a condition,
Refers to any method of ameliorating or otherwise beneficially changing the symptoms of a disorder or disease.
The effect may be prophylactic in terms of complete or partial prevention of the disease or its symptoms, and / or the effect may be partial or complete alleviation of signs or symptoms associated with the disease, disease May be therapeutic in terms of healing and / or reducing adverse effects resulting from the disease. Treatment also encompasses any pharmaceutical use of the composition herein.

As used herein, “heart failure” refers to an abnormal heart function in which the heart does not pump blood at the rate required for metabolic tissue requirements. Heart failure includes a wide range of disease states such as congestive heart failure, myocardial infarction, tachyarrhythmia, familial hypertrophic cardiomyopathy, ischemic heart disease, idiopathic dilated cardiomyopathy, myocarditis and the like . Heart failure is not limited to ischemic,
It can be caused by a number of factors, including congenital, rheumatic, viral, toxic, or idiopathic forms. Chronic cardiac hypertrophy is a serious morbidity that is a precursor to congestive heart failure and cardiac arrest.

As used herein, “ejection rate” or “EF” refers to the portion of blood that is pumped out of a full ventricle as a result of the heartbeat. It can be defined by the following formula:
(LV diastolic volume-LV systolic volume) / LV diastolic volume.

The present invention provides methods and compositions relating to the sustained release of neuregulin for the prevention, treatment or delay of various cardiovascular diseases or disorders, such as heart failure. The sustained release of neuregulin is
Enables simplification of dosing schemes, improves clinical efficacy, and attenuates adverse events associated with high blood levels of neuregulin, for example. Does sustained release of neuregulin over a period of time induce cardiomyocyte growth and / or differentiation and remodeling of myocyte sarcomeric and cytoskeletal structures, or expression of certain genes related to cell-cell adhesion? Or is intended to be maintained.

The sustained release of neuregulin provides a continuous therapeutic level of neuregulin over a period of time. In some embodiments, neuregulin is 1 hour, 2 hours, 3 hours, 4 hours, 5 hours,
Time, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, Release over a period of 22 hours, 23 hours, 24 hours or longer. In some embodiments, neuregulin is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14th, 15th, 16th
Day, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, 30th, or longer Over time. In another embodiment, neuregulin is released over a period of 1 week, 2 weeks, 3 weeks, 4 weeks or longer. This administration can optionally be performed for consecutive hours or for consecutive days or weeks, if desired. In another embodiment, neuregulin is 1 month, 2 months, 3 months, 4 months, 5 months, 6 months,
Released over a period of months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or longer. In another embodiment, neuregulin is released over a period of 1 year, 2 years, 3 years, 4 years, 5 years or longer. In some embodiments, neuregulin is
Release over a period of 1 hour to 2 weeks, 2 hours to 2 weeks, 4 hours to 24 hours, 4 days to 10 days. The amount of time that neuregulin is released over that period depends on various factors, such as the one or more sustained release techniques used.

Neuregulin can also be administered on a dosing schedule or “treatment cycle”. The daily dose of neuregulin in the treatment cycle is detailed below. The treatment cycle can last 2 days, 5 days, 7 days, 10 days, 2 weeks, 1 month, 3 months, 6 months, 1 year or longer. Generally, the recommended daily dose range of neuregulin per kg patient body weight in the methods of the invention for the conditions described herein is within the range of about 0.001 μg to about 1000 mg / day. In particular, the range of total daily dose per kg body weight of the patient is 0.001 μg / day to 15 mg / day, 0.005 μg / day to 10 mg / day, 0.01 μg / day to 5 mg / day, 0.1 μg / day to 1 mg / day 0.5 μg / day to 100 μg
/ Day, 1 μg / day to 10 μg / day, 1.2 μg / day to 2.4 μg / day, 1.2 μg / day to 2.2 μg / day, or 1.2 μg / day
Must be between days and 2.0 μg / day. In patient management, the treatment is initiated at a relatively low dose, perhaps about 0.1 μg to about 0.3 μg, and either a single dose or a divided dose, if necessary, depending on the patient's systemic response. As such, it can be increased up to about 1 μg to 1000 μg / day. As will be apparent to those skilled in the art, in some cases it may be necessary to use an active ingredient dose outside the range specified herein.

In certain embodiments, neuregulin is administered daily on each day of the treatment cycle. In certain embodiments, neuregulin is 3 days, 4 days, 5 days, 6 days, 7 days, 8 days,
It is administered continuously for 9 days, 10 days, 2 weeks, 1 month, 3 months, 6 months, 1 year or longer. In certain embodiments, neuregulin is administered to a patient for an induction regimen. In some optimized embodiments, the induction regimen is at least a continuous 3
, 5, 7, 10 or 15 days of administration of neuregulin. In some optimized embodiments, the induction regimen comprises administration of neuregulin for at least 2, 4, 6, 8, 10, 12, 16, 20, 24 hours daily. In some optimized embodiments, neuregulin is administered to the patient for a maintenance regimen of at least 3 months, 6 months, 12 months, 1 year, 5 years or longer after the induction regimen. The It is understood that other periods disclosed herein can be used for the induction or maintenance regimen.

In one embodiment, the invention provides 0.3 μg / kg / day to 3.0 μg of neuregulin to a mammal
A method of preventing, treating or delaying a cardiovascular disease or disorder in a mammal, comprising a sustained subcutaneous release in the amount of / kg / day, wherein the subcutaneous sustained release of neuregulin to the mammal Achieved through use. Sustained release of neuregulin can be provided by administration of neuregulin in a sustained release formulation, such as a formulation suitable for administration by use of a pump. In another embodiment,
The present invention prevents or treats a cardiovascular disease or disorder in a mammal, including subcutaneous administration of neuregulin in an amount of 0.3 μg / kg / day to 3.0 μg / kg / day in a sustained release to the mammal. Alternatively, a method of delaying is provided, wherein neuregulin subcutaneous release to the mammal is achieved by use of a pump.

In certain embodiments of the methods of the invention, the disease or disorder treated with neuregulin is heart failure, eg, in a mammal such as a human. In another embodiment, subcutaneous sustained release of neuregulin to the mammal is achieved by use of a syringe pump. The syringe pump can be a mini pump, such as, for example, an insulin pump.

In another embodiment of the method of the invention, neuregulin is from 1.2 μg / kg / day to 2.0 μg / kg / day.
It can be the amount of the day, or other amounts disclosed herein. In certain embodiments, neuregulin is in an amount of 1.2 μg / kg / day. In another specific embodiment, neuregulin is in an amount of 2.0 μg / kg / day. In another specific embodiment, neuregulin is in an amount of 6 EU / kg / day to 60 EU / kg / day. In another embodiment, neuregulin is 2
From 4 EU / kg / day to 40 EU / kg / day. In another embodiment, neuregulin is 24 EU.
The amount is / kg / day. In another embodiment, neuregulin is in an amount of 40 EU / kg / day.

In yet another embodiment of the methods of the invention, neuregulin can be administered to a mammal for an induction regimen. In one embodiment, the induction regimen comprises administration of neuregulin for at least 3, 5, 7, 10 or 15 consecutive days. It will be appreciated that other days of administration can be used if desired, as revealed herein.
In another embodiment, neuregulin is at least 2, 4, 6, 8, 10,
Can be administered for 12, 16, 20, 24 hours. As will be apparent herein, it is understood that other numbers of administration hours can be used if desired.

In another embodiment, neuregulin is administered to the patient for a maintenance regimen after the induction regimen. In one embodiment, the maintenance regimen is at least 3 after the induction regimen.
Administration of neuregulin can be included for months, 6 months, 12 months, 5 years or even longer. In another embodiment, the maintenance regimen comprises repeated induction regimens every 3 months, 6 months or 12 months.

In yet another embodiment, sustained release of neuregulin to the mammal increases the ejection fraction (EF) value of the mammal. Ejection rate (EF) represents the volume ratio of pumped blood in the left and right ventricles with each heart beat or cardiac cycle. The method for measuring ejection fraction is well known to those skilled in the art.

In yet another embodiment, sustained release of neuregulin to the mammal decreases the left ventricular end-diastolic volume (LVEDV) of the mammal. As is well known in the art, end-diastolic volume (ED
V) is the volume of blood in the right and / or left ventricle at the time of afterload or fullness (expansion). In another embodiment, the sustained release of neuregulin to the mammal is the left ventricular end systolic volume of the mammal.
Reduce (LVESV). As is well known in the art, end systolic volume (ESV) is reduced (c
The volume of blood in the ventricle at the end of ontraction or systole and at the start of fullness or dilation. Methods for measuring LVEDV and / or LVESV are well known to those skilled in the art.

In yet another embodiment of the method of the present invention, the sustained release of neuregulin to the mammal comprises
Improve the 6-minute walking distance (6MWD) of mammals. In yet another embodiment, the sustained release of neuregulin to the mammal improves the quality of life of the mammal. The effectiveness of neuregulin in improving heart disease measurements and / or improved patient outcomes is described herein in the Examples.

The present invention additionally provides a kit for preventing, treating or delaying a cardiovascular disease or disorder in a mammal comprising a neuregulin composition or formulation and a pump. The kit can be used, for example, to treat a patient having a disease or disorder that is heart failure.
The patient can be a mammal, such as a human. In kit embodiments, the pump can be a syringe pump. In certain embodiments, the pump can be a minipump. In another specific embodiment, the pump can be an insulin pump.

The characteristics of patients having a disease or disorder such as heart disease or heart failure are well known to those skilled in the art (
For example, “Cecil Textbook of Medicine”, 20th edition, edited by Bennett and Plum, WB Saunders, Philadelphia (1996); “Harrison's Princi”
ples of Internal Medicine), 14th edition, edited by Fauci et al., McGraw-Hill, San Francisco (1998)). One of ordinary skill in the art, such as a physician, can readily determine a patient with a disease or disorder suitable for treatment with the methods of the invention that provides sustained release of neuregulin.

It is well known in the art that patient heart failure can be classified according to the severity of their symptoms. The most commonly used classification system is the New York Heart Association (NYHA) cardiac function classification. This places the patient in one of the following four categories based on how much the patient is restricted during physical activity: Class I: has heart disease but does not limit physical activity patient. Daily physical activity does not cause undue fatigue, palpitation, dyspnea or angina pain; Class II: Patients with heart disease resulting in slight limitation of physical activity. The patient has no complaints at rest. Daily physical activity results in fatigue, palpitation, dyspnea or angina pain; Class III: Patients with heart disease that cause significant limitations in physical activity. Patient has no complaints at rest. Lighter daily activities cause fatigue, palpitation, dyspnea or angina pain; Class IV: Patients with heart disease who are unable to perform any physical activity without a complaint. Symptoms of heart failure or angina syndrome may be present even at rest. Complaints increase when working on some physical activity. In some embodiments, NYHA-classified patients (Class I-Class IV
) Are all suitable for the method of the invention. In some preferred embodiments, NYHA classified class II and / or class III patients are suitable for the methods of the invention.

In certain embodiments, neuregulin in a treatment cycle is administered on the first day of the cycle, and the cycle ends with no neuregulin administered for more than one day. In some embodiments, neuregulin is administered daily for 3, 5, 7, 10 or 15 days;
This is followed by a drug holiday in the treatment cycle.

It is understood that modifications that do not substantially affect the activity of the various embodiments of this invention are also provided within the definition of the invention provided herein. Accordingly, the following examples are intended to illustrate but not limit the present invention.

(Example)
(Example 1: Randomized parallel group double-blind multicenter placebo comparison study evaluating the efficacy and safety of recombinant human neuregulin 1 in subjects with stable chronic heart failure)
(1. Introduction)
To evaluate the efficacy and safety of recombinant human neuregulin-1 for subcutaneous infusion for chronic heart failure, a phase II randomized, parallel group, double-blind, placebo-controlled trial has been It was conducted. A total of 67 patients with stable chronic heart failure in NYHA class II or III participated. Subjects were examined for their implantable cardioverter defibrillators (ICDs) between 1 and 7 days before being randomized to the drugs. Subjects were randomized to one of three treatment arms at the end of screening after baseline cardiac computed tomography (CT). The study consists of five periods, which are the screening and baseline period (Study Day 21--
(Day 3), treatment period (study days 1-10, daily infusion start time 8am ± 2h), discharge (11
Day), follow-up period (Studies 30, 90 and 180 ± 5 days), and the last follow-up visit by day 365 (± 5 days), lasting approximately 12 months. All subjects were instructed to adhere to their latest stable cardiac regimen for the duration of the study.

(2. Diagnosis and main participation criteria)

A stable regimen of ACEI / angiotensin receptor blocker (ARB), beta-blocker, and / or diuretic for at least 3 months before the subject has NYHA Class II or III heart failure and receives study drug These subjects were considered for enrollment if they were in and expected to maintain a stable regimen throughout the treatment period. Subjects must have ICD implanted for at least 3 months prior to receiving study drug and have a left ventricular ejection fraction (LVEF) ≤40% as determined at screening by 2-D echocardiography. I was asked.

(3. Product, dose, duration, administration method, and batch / lot number)

From day 1 to day 10, subjects received one of the following treatments by subcutaneous injection: placebo (
Lot number: TC2952, 250 μg / vial) or Neucardin ™ (lot number: TC2965, 25
0 μg / 5000 EU / vial) dose 1.2 μg / kg / day (24 EU / kg / day) or 2.0 μg / kg / day (40 EU / kg
/Day).

Study drug identification: Neucardin ™ (lot number: TC2965) and matching placebo (
Lot number: TC2952) was supplied in clear glass vials containing 250 μg of active drug or placebo per vial. The active drug and matching placebo were white to yellowish white powder. The study drug appears to be a clear, colorless solution that is essentially free of visible particles to prepare a daily dose of 1.2 μg / kg, 2.0 μg / kg, and placebo, subject weight (kg
) And prepared according to the randomized code provided. The storage temperature is 2-8 ° C,
And the drug was shielded from light and kept out of reach of children.

SC infusion pump: Medtronic Paradigm 722 insulin pump. Using a Medtronic pump container, 1.6 mL of dissolved drug was collected into the container and the pump flow rate was 0.2 ml / hr for 8 hours.

(4. Evaluation criteria)

Efficacy: Efficacy assessment was based on cardiac CT at baseline and 30 days; screening and baseline, and days 30, 90, 180 and 365, NYHA classification, 6-minute walk test, quality of life questions Votes (Kansas City Cardiomyopathy Questionnaire and NT-proBNP levels; and 2-D echocardiograms at screening and baseline, at days 30 and 90, were included.

Safety: Safety assessment includes adverse events (AE), adverse reactions (ADR), serious adverse events (SAE), vital signs, physical examination, pulse oximetry, ECG parameters (eg, QTc, QRS, HR, PR, R
R, T-wave flattening / reversal, ST-elevation), anti-Neucardin ™ antibody levels, pericardial fluid measured by cardiac CT (mL, small, medium, large), ICD questionnaire (not (With or without appropriate fibrosis)
, 2D echocardiographic pericardial fluid (mL, small, medium, large), and laboratory parameters (chemistry,
Monitoring hematology, and urology). In cardiology, QTc is
QT interval, which is a measure of the time between the beginning of the Q wave and the end of the T wave in the heart's electrical cycle. The QT interval represents ventricular electrical polarization and repolarization. The extended QT interval is
It is a marker of the possibility of ventricular tachyarrhythmia such as de pointe and risk factors for sudden death. Q waves, R waves and S waves occur from one to the next, all of which do not appear to be all leading, reflect a single event and are therefore usually considered together. The Q wave is an arbitrary downward run after the P wave. The R wave is the subsequent upside shake and the S wave is any downside after the R wave. The T wave follows the S wave, and in some cases, the T wave is followed by an additional U wave. The heart rate (HR) is a heart beat rate, specifically, the heart beat rate per unit time. The PR interval is generally also referred to as a PQ interval when a Q wave is measured by ECG. RR is EC
This is the interval between successive Rs in G hours. The fluctuation of the RR interval that exists at rest represents the fluctuation for each beat in the autonomic inputs of the heart. CT refers to X-ray computed tomography. ICD refers to an implantable defibrillator.

(5. Results) The results are shown below.

(5.1 LVEF)
Table 1: Results of changes in absolute values of LVEF% and LVEF% at baseline and on day 30

The LVEF% value decreased in the placebo group, but this value increased in both neuregulin groups (see Figure 1 and Table 1). Mean absolute value changes were in placebo, 1.2 μg / kg and 2
In the 0.0 μg / kg group, -0.82%, 2.53%, and 3.20%, respectively (see Figure 2 and Table 1), indicating that Neucardin (TM) improved cardiac function with the subcutaneous injection route. ing.

(5.2 LVEDV)
Table 2: Results of changes in absolute values of LVEDV (ml) and LVEDV (ml) at baseline and on day 30

LVEDV values increased in the placebo group, but in the 2.0 μg / kg group, the increase in LVEDV was not as great as the increase in the placebo group, and this value was significantly reduced in the 1.2 μg / kg group (Figure 3 and (See Table 2). The mean absolute value changes were 10.22 ml, -8.16 ml and 2.36 ml in the placebo group, 1.2 μg / kg group and 2.0 μg / kg group, respectively (see FIG. 4 and Table 2). Regarding the LVEDV value, the 1.2 μg / kg group was superior to the 2.0 μg / kg group.

(5.3 LVESV)
Table 3: Results of changes in absolute values of LVESV (ml) and LVESV (ml) at baseline and on day 30

LVESV increased in the placebo group but decreased in both neuregulin groups (
(See Figure 5 and Table 3). The mean absolute value changes were 9.33 ml, -10.58 ml and -5.19 ml in the placebo group, 1.2 μg / kg group and 2.0 μg / kg group, respectively (see FIG. 6 and Table 3). Regarding LVESV value,
The 1.2 μg / kg group was superior to the 2.0 μg / kg group. Both LVEDV and LVESV data are
It has been shown that ardin ™ effectively reversed ventricular remodeling in CHF patients via the subcutaneous injection route.

(5.4 6-minute walking test)
Table 4: Increased walking distance (m) and post-walking dyspnea and post-walking fatigue results at 30, 90, 180 and 365 days compared to baseline

Walking distance increased in the 1.2 μg / kg group (41.4 m on day 30, 52.2 m on day 90, 47.7 m on day 180, 36
62.2m on day 5) was the longest in all three groups, and increased walking distance in the placebo group (19.2m on day 30, 21.6m on day 90, 30.5m on day 180, day 365) 39.4m) is 2.0μg / kg
It was longer than the group (1.7m on day 30, -2.0m on day 90, 11.7m on day 180, -24.4m on day 365) (Fig. 7
And Table 4). The observed increase in walking distance observed in the 1.2 μg / kg / day group exceeded that expected based on previous studies using intravenous administration of neuregulin. Both neuregulin groups were superior to the placebo group in terms of post-walking dyspnea and fatigue results on day 30 and 90 (see FIGS. 8 and 9 and Table 4).

(5.5 Quality of life on days 30, 90, 180 and 365)
Table 5: Quality of life analysis

As can be seen in FIG. 10, the quality of life scores are the placebo group, the 1.2 μg / kg group and the 2.0 μg / kg group.
There was an increase of 4.825, 15.152 and 9.649, respectively, in the kg group (see also Table 5). A higher score means a better quality of life. As can be seen in Table 5, the quality of life score of the 1.2 μg / kg group was the highest of these three groups. The scores for all three groups increased, but the 1.2 μg / kg group increased more than the placebo group (see FIG. 10). The observed increase in the quality of life score observed in the 1.2 μg / kg / day group exceeded that predicted based on previous studies using intravenous administration of neuregulin.

(5.6 Results of NT-proBNP median change on days 30, 90, 180 and 365 at baseline)
Table 6: NT-proBNP median change (PG / ML)

Since NT-proBNP is typically higher in patients with worse outcomes, it is widely used as a marker for the diagnosis or prognosis of heart failure. As can be seen in Table 6, 1.2
The level of NT-proBNP in the μg / kg group was the lowest of the three groups, and the 1.2 μg / kg group decreased much more than the placebo group.

表8：ベースライン時と比較したNYHA分類で1度以上変化した患者の数及び割合

(5.7 NYHA classification on the 30th day)
Table 7: NYHA classification percentage at baseline and on day 30

Table 8: Number and percentage of patients with one or more changes in NYHA classification compared to baseline

As can be seen in FIG. 11 and Tables 7 and 8, more patients were reduced more than once in the NYHA classification by Neucardin ™ treatment. The observed decline in the NYHA classification exceeded that predicted based on previous studies using intravenous administration of neuregulin.

(5.8 Safety evaluation)
Table 9: General summary of adverse events (AEs)

As seen in Table 9, safety data indicate that Neucardin (TM) administration increases the incidence of adverse events, but most of these are mild to moderate, especially in the 1.2 μg / kg group. Indicated. In the 1.2 μg / kg group, the incidence of serious adverse events decreased, which was
In (TM) treatment suggests that the overall situation in CHF patients has improved.

Throughout this application various publications are cited. In order to more fully describe the state of the art to which this invention pertains, the disclosures of these publications are incorporated herein by reference in their entirety. Although the invention has been described with reference to the embodiments presented above, it should be understood that various modifications can be made without departing from the spirit of the invention.

Throughout this application various publications are cited. In order to more fully describe the state of the art to which this invention pertains, the disclosures of these publications are incorporated herein by reference in their entirety. Although the invention has been described with reference to the embodiments presented above, it should be understood that various modifications can be made without departing from the spirit of the invention.
The present application provides an invention having the following configuration.
[Configuration 1]
A method for preventing, treating or delaying a cardiovascular disease or disorder in a mammal, comprising:
Including subcutaneous sustained release of neuregulin in an amount of 0.3 μg / kg / day to 3.0 μg / kg / day to a mammal, where
Said method wherein subcutaneous subcutaneous release of neuregulin to said mammal is achieved by use of a pump
.
[Configuration 2]
The method according to configuration 1, wherein the disease or disorder is heart failure.
[Configuration 3]
The method of constitution 1, wherein the mammal is a human.
[Configuration 4]
Subcutaneous sustained release of neuregulin to the mammal is achieved through the use of a syringe pump.
The method according to Configuration 1.
[Configuration 5]
5. The method according to configuration 4, wherein the syringe pump is a mini pump.
[Configuration 6]
6. The method of configuration 5, wherein the minipump is an insulin pump.
[Configuration 7]
The method of configuration 1, wherein the neuregulin is in an amount of 1.2 μg / kg / day to 2.0 μg / kg / day.
[Configuration 8]
The method of configuration 1, wherein the neuregulin is in an amount of 1.2 μg / kg / day.
[Configuration 9]
The method of configuration 1, wherein the neuregulin is in an amount of 2.0 μg / kg / day.
[Configuration 10]
The method of configuration 1, wherein the neuregulin is in an amount of 6 EU / kg / day to 60 EU / kg / day.
[Configuration 11]
The method of configuration 1, wherein the neuregulin is in an amount of 24 EU / kg / day to 40 EU / kg / day.
[Configuration 12]
The method of configuration 1, wherein the neuregulin is in an amount of 24 EU / kg / day.
[Configuration 13]
The method of configuration 1, wherein the neuregulin is in an amount of 40 EU / kg / day.
[Configuration 14]
The method of configuration 1, wherein the neuregulin is administered to a mammal for an induction regimen
Law.
[Configuration 15]
The induction regimen is administered at least 3, 5, 7, 10 or 15 days of neuregulin administration.
15. The method of configuration 14, comprising:
[Configuration 16]
15. The method of configuration 14, wherein the induction regimen comprises administration of 10 consecutive days of neuregulin.
.
[Configuration 17]
The neuregulin is at least 2, 4, 6, 8, 10, 12, 16, 20, 24 hours continuously every day
The method of configuration 14, wherein the method is administered.
[Configuration 18]
15. The method of configuration 14, wherein the neuregulin is administered continuously for 8 hours daily.
[Configuration 19]
The neuregulin is administered to a patient for a maintenance regimen after an induction regimen.
The method according to claim 14.
[Configuration 20]
The maintenance regimen is at least 3 months, 6 months, 12 months, 5 years or longer after the induction regimen.
20. The method of configuration 19, further comprising administration of neuregulin for a longer time.
[Configuration 21]
Configuration 19 wherein the maintenance regimen comprises repeated induction regimens every 3 months, 6 months or 12 months
The method described.
[Configuration 22]
The controlled release of neuregulin to the mammal increases the value of the ejection fraction (EF) of the mammal.
The method according to composition 1.
[Configuration 23]
Sustained release of neuregulin to the mammal reduces the left ventricular end-diastolic volume (LVEDV) of the mammal.
The method according to Configuration 1, which is less.
[Configuration 24]
Sustained release of neuregulin to the mammal reduces the left ventricular end systolic volume (LVESV) of the mammal.
The method according to Configuration 1, which is less.
[Configuration 25]
Sustained release of neuregulin to the mammal improves the 6-minute walking distance (6MWD) of the mammal
The method according to Configuration 1.
[Configuration 26]
Constituent 1, wherein sustained release of neuregulin to the mammal improves the quality of life of the mammal
The method of publication.
[Configuration 27]
Cardiovascular disease or in mammals comprising a neuregulin composition or formulation and a pump
Kit for prevention, treatment or delay of disorders.
[Configuration 28]
28. The kit according to configuration 27, wherein the disease or disorder is heart failure.
[Configuration 29]
28. The kit according to configuration 27, wherein the mammal is a human.
[Configuration 30]
28. The kit according to configuration 27, wherein the pump is a syringe pump.
[Configuration 31]
28. The kit according to configuration 27, wherein the pump is a mini pump.
[Configuration 32]
28. The kit according to configuration 27, wherein the pump is an insulin pump.

Claims (32)

A method for preventing, treating or delaying a cardiovascular disease or disorder in a mammal, comprising subcutaneously releasing neuregulin in an amount of 0.3 μg / kg / day to 3.0 μg / kg / day to the mammal, Wherein said subcutaneous release of neuregulin to said mammal is achieved by use of a pump.   2. The method of claim 1, wherein the disease or disorder is heart failure.   2. The method according to claim 1, wherein the mammal is a human. 2. The method of claim 1, wherein subcutaneous sustained release of neuregulin to the mammal is achieved by use of a syringe pump.   5. The method of claim 4, wherein the syringe pump is a mini pump.   6. The method of claim 5, wherein the minipump is an insulin pump. 2. The method of claim 1, wherein the neuregulin is in an amount of 1.2 [mu] g / kg / day to 2.0 [mu] g / kg / day.   The method of claim 1, wherein the neuregulin is in an amount of 1.2 μg / kg / day.   The method of claim 1, wherein the neuregulin is in an amount of 2.0 μg / kg / day.   2. The method of claim 1, wherein the neuregulin is in an amount of 6 EU / kg / day to 60 EU / kg / day.   2. The method of claim 1, wherein the neuregulin is in an amount of 24 EU / kg / day to 40 EU / kg / day.   2. The method of claim 1, wherein the neuregulin is in an amount of 24 EU / kg / day.   2. The method of claim 1, wherein the neuregulin is in an amount of 40 EU / kg / day. 2. The method of claim 1, wherein the neuregulin is administered to a mammal for an induction regimen. 15. The method of claim 14, wherein the induction regimen comprises at least 3, 5, 7, 10 or 15 days of neuregulin administration. 15. The method of claim 14, wherein the induction regimen comprises 10 consecutive days of neuregulin administration. 15. The method of claim 14, wherein the neuregulin is administered daily for at least 2, 4, 6, 8, 10, 12, 16, 20, 24 hours.   15. The method of claim 14, wherein the neuregulin is administered daily for 8 hours consecutively. 15. The method of claim 14, wherein the neuregulin is administered to a patient for a maintenance regimen after an induction regimen. 20. The method of claim 19, wherein the maintenance regimen comprises administration of neuregulin for at least 3 months, 6 months, 12 months, 5 years or even longer after the induction regimen. The maintenance regimen comprises repeated induction regimens every 3 months, 6 months or 12 months.
19. The method according to 19. 2. The method of claim 1, wherein the sustained release of neuregulin to the mammal increases the value of the ejection fraction (EF) of the mammal. 2. The method of claim 1, wherein the sustained release of neuregulin to the mammal reduces the left ventricular end-diastolic volume (LVEDV) of the mammal. 2. The method of claim 1, wherein the sustained release of neuregulin to the mammal reduces the left ventricular end systolic volume (LVESV) of the mammal. 2. The method of claim 1, wherein the sustained release of neuregulin to the mammal improves the 6-minute walking distance (6MWD) of the mammal. 2. The sustained release of neuregulin to the mammal improves the quality of life of the mammal.
The method described. A kit for the prevention, treatment or delay of a cardiovascular disease or disorder in a mammal comprising a neuregulin composition or formulation and a pump.   28. The kit of claim 27, wherein the disease or disorder is heart failure.   28. The kit of claim 27, wherein the mammal is a human.   28. The kit of claim 27, wherein the pump is a syringe pump.   28. The kit of claim 27, wherein the pump is a minipump.   28. The kit of claim 27, wherein the pump is an insulin pump.

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